Study unravels mechanism behind omega-3 fatty acid-induced improvement in NASH and liver health

A research team led by Jyothi Padiadpu, College of Pharmacy, Oregon State University, Corvallis, OR, USA, revealed that ω3-PUFA reduces hepatic dysfunction in NASH by lowering betacellulin (BTC), a protein growth factor that contributes to liver fibrosis and progression to cirrhosis and liver cancer.

"These newfound mechanistic insights hold the potential to facilitate the development of innovative therapies targeting the BTC pathway for NASH treatment and prevention of liver cancer," the researchers wrote. "The gene expression signature triggered by BTC is promising as a potential biomarker for guiding clinical trials involving omega-3 PUFA, potentially advancing personalized medicine for liver disease management."

Previous studies have shown that supplementing diets with ω3 polyunsaturated fatty acids (PUFA) can reduce hepatic dysfunction in NASH, but the molecular underpinnings of this action were elusive. Therefore, the researchers used multi-omic network analysis that identifies critical molecular pathways involved in ω3 PUFA effects in a preclinical mouse model of western diet-induced NASH.

Since NASH is a precursor of liver cancer, they also performed a meta-analysis of human liver cancer transcriptome data to evaluate which aspects of NASH pathogenesis leading to cancer are reversed by omega-3 polyunsaturated fatty acids.

The key takeaways from the study are as follows:

• BTC, an epidermal growth factor–binding protein, was consistently upregulated in liver cancer and downregulated by omega-3 polyunsaturated fatty acids in mice and humans with NASH.
• BTC promotes NASH fibrosis by activating dormant hepatic stellate cells to produce transforming growth factor beta-2 and increase collagen production. It also exacerbates toll-like receptor-dependent inflammatory processes in NASH.
• By downregulating BTC, omega-3 polyunsaturated fatty acids have therapeutic potential in NASH and could serve as a novel drug target.

"Taken together, our findings indicate that suppression of betacellulin is one of the key mechanisms associated with the anti-fibrotic and anti-inflammatory effects of ω3 PUFA on NASH," the research team concluded.

"BTC represents a candidate master regulator inducing two most important factors (integrins and collagens) contributing to liver fibrosis and consequently promoting liver cancer," the researchers write.

"Future studies should investigate if BTC-triggered gene expression signatures can serve as biomarkers guiding personalized therapy, as targets of new NAFLD/NASH drugs, and finally as predictors of the risk of hepatic cancer in humans."

The study authors report no limitations. However, the findings are based on human transcriptome data and mouse models.

Reference:

Padiadpu J, Garcia-Jaramillo M, Newman NK, Pederson JW, Rodrigues R, Li Z, Singh S, Monnier P, Trinchieri G, Brown K, Dzutsev AK, Shulzhenko N, Jump DB, Morgun A. Multi-omic network analysis identified betacellulin as a novel target of omega-3 fatty acid attenuation of western diet-induced nonalcoholic steatohepatitis. EMBO Mol Med. 2023 Nov 8;15(11):e18367. doi: 10.15252/emmm.202318367. Epub 2023 Oct 20. PMID: 37859621; PMCID: PMC10630881.